Outcomes of Bypass Surgery in Adult Moyamoya Disease by Onset Type

Key Points Question What are the outcomes of bypass surgery in patients with adult moyamoya disease (MMD) with varying onset types? Findings In this population-based cohort study of 19 700 patients, bypass surgery was associated with reduced risk of death and hemorrhagic stroke in hemorrhagic MMD, ischemic stroke in ischemic MMD, and death in asymptomatic MMD; however, bypass was associated with an increased risk of hemorrhagic stroke in asymptomatic MMD. Both direct and indirect bypass showed similar outcomes in asymptomatic and hemorrhagic MMD, except that only direct bypass was associated with a reduced risk of ischemic stroke in ischemic MMD. Meaning These findings suggest that it may be beneficial to tailor management strategies for patients with adult MMD based on onset type.


Introduction
[6][7] Moyamoya disease presents with a bimodal age distribution, at approximately 10 years and 30 to 50 years. 1,2Bypass surgery usually improves prognosis in pediatric patients.However, the benefits and the optimal modality of bypass in adult patients remain controversial.Randomized clinical trials and large studies suggesting the superiority of a specific management modality have been scarce.They are limited by the small size or heterogeneity (eg, children or adults, presenting symptoms, and varying disease progression status on angiographic findings) of the cohorts and present outcomes without considering their onset types.
To address these limitations, we used the Korean Health Insurance Review and Assessment (HIRA) database, which has a special registration program for rare intractable diseases (RID), including MMD.We categorized the patients based on onset type (asymptomatic, ischemic, and hemorrhagic MMD) and compared the effect of bypass surgery (direct or indirect) with conservative management in adult patients with MMD in terms of the risk for death, hemorrhagic stroke (HS), and ischemic stroke (IS).This approach aims to provide a more comprehensive understanding of the optimal management for adult patients with MMD and guide clinicians in making tailored treatment decisions.

Study Participants, Comorbidity, and Outcome Variables
][10] The study was approved by the Ajou University Hospital Institutional Review Board.Access to the HIRA database was approved by the Korea National Health Insurance Sharing Service.Informed consent was waived owing to the use of deidentified data.The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We identified patients newly diagnosed with MMD from January 1, 2008, to December 31, 2020, and we followed them up to December 31, 2021.A 1-year washout period (2007-2008) was used to prevent prevalent cases from interfering with the data for inclusion, exclusion, and confounding factors. 11,12We improved the accuracy of patient identification by using specific operational definitions.The diagnosis of MMD was established if International Statistical Classification of Diseases, Tenth Revision (ICD-10), code I67.5 and RID code V128 were newly recorded at least once in the database at hospital discharge or more than twice in the outpatient department.
Patients with bilateral and unilateral involvement were both included in our data analysis. 10The exclusion criteria were as follows: (1) younger than 15 years 11 ; (2) a history of direct or indirect bypass surgery before a diagnosis of MMD; (3) cardiac arrhythmia (ICD-10 code I48) that may cause thromboembolic complications; (4) cancers (ICD-10 codes C); (5) unstable angina or myocardial infarction (ICD-10 codes I20-I25) within the past 12 months; and (6) bleeding diathesis (ICD-10 codes D65-D69).We classified the identified patients into 3 groups based on the following onset types: hemorrhagic, ischemic, and asymptomatic MMD.We categorized the patients according to the following management strategies: direct bypass, indirect bypass, and conservative management (Figure 1).The primary outcome was the occurrence of death; secondary outcomes were HS or IS based on ICD-10 codes.Baseline comorbidities were defined as conditions diagnosed within 1 year before the MMD diagnosis date: hypertension, type 2 diabetes, and dyslipidemia [13][14][15][16]

Statistical Analysis
Data were analyzed from January 2 to April

Baseline Characteristics
Of Kaplan-Meier curves were used to compare the risks of death, HS, and IS between the bypass and conservative management groups (Figure 2 and eFigure 1 in Supplement 1) and among the direct and indirect bypass and conservative management groups (eFigure 2 in Supplement 1).Compared with conservative management, bypass was associated with a reduced risk of death in all MMD (P < .001)(eFigure 1 in Supplement 1); a reduced risk of death and HS in hemorrhagic MMD (P < .001)2); a reduced risk of IS in ischemic MMD (P < .001);and a reduced risk of death (P < .001)and IS (P = .04)in asymptomatic MMD.Notably, bypass was associated with increased risk of HS in asymptomatic MMD (P < .001).Among direct bypass, indirect bypass, and conservative management (eFigure 2 in Supplement 1), direct or indirect bypass was associated with reduced risk of death (P < .001),HS (P = .007),and IS (P = .04)in all MMD, and a similar association was found in other subgroups except IS in asymptomatic MMD (P = .10).Cox proportional hazards regression analysis was performed to estimate the HRs for the risk of death, HS, and IS in each MMD subgroup between the bypass (direct and indirect) and conservative groups (

Sensitivity Analysis, Propensity Score-Matching Analysis, and Stratified Analysis
Sensitivity analysis was performed to validate the definitions of MMD subgroups for the risks of death, HS, and IS.All patients with MMD were reclassified into 3 subgroups according to their records for 1, 3, and 12 months prior to the occurrence of the MMD code.All results aligned with those derived using our primary methods (eTable 6 in Supplement 1).
Regarding controlling covariates, the bypass group was propensity score matched 1:1 with the conservative group (Table 2).Baseline covariates were compared across the matched patient groups before and after matching.They were well balanced based on absolute mean differences with age, sex, hypertension, diabetes, and dyslipidemia (eFigure 3 in Supplement 1).The Kaplan-Meier curves were drawn to compare survival curves, and the log-rank test assessed the difference with a matched cohort.The association of a bypass with death, HS, and IS demonstrated similar trends observed in all cohorts as found in the primary analysis (eFigure 4 in Supplement 1).Furthermore, we stratified patients by each category of covariates.In most cases, age was a significant factor to interact with outcomes.Bypass was associated with a reduced risk of death compared with conservative

Discussion
To our knowledge, this study is the largest population-based retrospective longitudinal cohort study of adult MMD demonstrating the outcomes of bypass surgery in terms of death, HS, and IS according to the onset types.We present the results of 19 700 patients with a median follow-up of 5.74 (IQR, 2.95-9.42)years.Bypass was associated with a reduced risk of death and HS in hemorrhagic MMD, reduced risk of IS in ischemic MMD, and reduced risk of death in asymptomatic MMD.However, bypass was associated with an increased risk of HS in asymptomatic MMD.Both direct and indirect bypass demonstrated similar effects, except that only direct bypass was associated with a reduced risk of IS in ischemic MMD.These findings emphasize the need for individualized management strategies tailored to different clinical presentations.

Management of Asymptomatic MMD in Adults
Data on the long-term prognosis of conservative management for adult patients with MMD are limited.Some studies [17][18][19][20][21][22] have described the outcomes of conservative treatment for patients with asymptomatic or hemodynamically stable MMD.In a series of 113 adult patients with MMD, 17 the disease progression rate was reported to be approximately 20% over 6 years.9][20][21] In a recent multicenter study in Japan with 103 asymptomatic adult patients with MMD, 22 the annual risk of stroke was 1.0% in the first 5 years, predominantly hemorrhage in nature.In the present study, the annual rates of HS and IS were 1.21 and 0.56 per 100 person-years, respectively, in patients with asymptomatic MMD and conservative management (eTable 8 in Supplement 1).Bypass surgery was associated with a reduced risk of death and IS, but an increased risk of HS in asymptomatic MMD.
These findings may provide information on the long-term prognosis of adults with conservatively managed asymptomatic MMD and emphasize the need for careful consideration of individual patient characteristics and disease progression when determining the treatment strategy.

Management of Ischemic and Hemorrhagic MMD in Adults
The treatment in patients with MMD consists of augmenting blood flow and relieving hemodynamic stress on moyamoya vessels to prevent future stroke. 23Bypass surgery is usually considered for patients with recurrent clinical symptoms due to apparent cerebral ischemia or decreased regional cerebral blood flow, vascular response, Suzuki stage, 24,25 and reserve in perfusion studies 26 and may help prevent further IS. 27In adults with ischemic MMD, a diminishment of moyamoya vessels has been observed on angiography after bypass surgery. 28It is likely that the dominant bypass flow reduces the burden on moyamoya vessels, which results in the relief of hemodynamic stress.0][31] In reports examining adults with MMD treated with indirect bypass, 2,32-36 0 to 14.3% of patients experienced a postoperative stroke each year, and the weighted mean annual rate of stroke was 5.6%.In the present study, bypass surgery was associated with a reduced risk of death and IS, and IS risk remained after adjustment, which is consistent with previous reports. 27,37 adults with hemorrhagic MMD, the benefits of bypass remain unclear.Long-term hemodynamic stress to collateral vessels is thought to induce vascular abnormalities, such as microaneurysms, leading to hemorrhage. 1,38Diminishing of these abnormalities was observed after bypass surgery. 39,40

Figure 2 .
Figure 2. Patient Outcomes After Bypass Surgery
1, 2023.Kaplan-Meier survival curves were generated and compared using the log-rank test.The proportional hazard assumption was tested by Schoenfeld residuals, and Cox proportional hazards regression models were adopted to calculate hazard ratios

Table 1 .
Outcomes After Bypass Surgery in Each MMD Subgroup

Table 2 .
Outcomes in Each MMD Subgroup According to Management Modality With 1:1 Propensity Score-Matched Cohort Abbreviations: AHR, adjusted hazard ratio; MMD, moyamoya disease; NA, not applicable.